Advances in Clinical Care with Contemporary Cardiac SPECT.

State of the art of cardiac SPECT imaging continues to advance. Contemporary clinical applications of cardiac SPECT are reviewed and illustrated. Beyond traditional stress and rest myocardial perfusion imaging, the role of digital SPECT technology, ultra low dose imaging with efficient stress first / stress only if normal imaging, deep learning algorithms relative to coronary angiography and SPECT CT, sourceless emission attenuation correction, myocardial blood flow and blood flow reserve to assess ischemic jeopardy, culprit ischemic territories, and cardiac allograft vasculopathy, advanced methods of SPECT detection of amyloid cardiomyopathy, resting MPI to define pre-operative regional scar prior to operative ablation, parametric radionuclide ventriculography to quantify dyssynchrony and benefit of biventricular pacing, assessment of treatment response of RV and LV function in patients with pulmonary hypertension, dual isotope MIBG imaging to assess cardiac risk, and the value proposition of real world effectiveness of SPECT cardiac imaging are illustrated.

Neuromuscular manifestations of wild type transthyretin amyloidosis: a review and single center's experience.

Transthyretin amyloidosis (ATTR) is a condition defined by accumulation of insoluble transthyretin amyloid deposits in multiple organs, especially in the peripheral nerve and heart muscle. ATTR may result from transthyretin mutations (variant ATTR or ATTRv) or may occur with normal transthyretin genotype (wild type ATTR or ATTRwt). ATTRwt was previously known as "senile amyloidosis" and causes cardiomyopathy which may lead to heart failure with a preserved ejection fraction, affecting predominantly elderly men. The exact prevalence of ATTRwt in the general population remains unclear, but its occurrence may be underestimated in women. It was observed that a proportion of ATTRwt cardiomyopathy patients may develop slowly progressing neuropathy that is milder and indolent in comparison with typical progressive neuropathy associated with ATTRv. Furthermore, the causality of neuropathy is often uncertain in patients with ATTRwt. Neuropathy symptoms, including distal sensory loss, unsteadiness and (neuropathic) pain are common in elderly patients with multiple potential causes, and as ATTRwt patients are typically older, relatively high prevalence of peripheral neuropathy is expected with frequent comorbidities. Relatively high prevalence of ATTRwt in elderly population contrasts few documented cases of neuropathy caused by ATTRwt, and there is uncertainty whether ATTRwt neuropathy is an infrequent occurrence or a significant manifestation of multisystemic ATTRwt. We review neurologic and musculoskeletal manifestations of ATTRwt and present clinical features of a single center cohort of ATTRwt patients with suspected peripheral neuropathy.

Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Transthyretin amyloid cardiomyopathy is characterized by the deposition of misfolded monomeric transthyretin (TTR) in the heart. Acoramidis is a high-affinity TTR stabilizer that acts to inhibit dissociation of tetrameric TTR and leads to more than 90% stabilization across the dosing interval as measured ex vivo. METHODS: In this phase 3, double-blind trial, we randomly assigned patients with transthyretin amyloid cardiomyopathy in a 2:1 ratio to receive acoramidis hydrochloride at a dose of 800 mg twice daily or matching placebo for 30 months. Efficacy was assessed in the patients who had an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m2 of body-surface area. The four-step primary hierarchical analysis included death from any cause, cardiovascular-related hospitalization, the change from baseline in the N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, and the change from baseline in the 6-minute walk distance. We used the Finkelstein-Schoenfeld method to compare all potential pairs of patients within strata to generate a P value. Key secondary outcomes were death from any cause, the 6-minute walk distance, the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary, and the serum TTR level. RESULTS: A total of 632 patients underwent randomization. The primary analysis favored acoramidis over placebo (P<0.001); the corresponding win ratio was 1.8 (95% confidence interval [CI], 1.4 to 2.2), with 63.7% of pairwise comparisons favoring acoramidis and 35.9% favoring placebo. Together, death from any cause and cardiovascular-related hospitalization contributed more than half the wins and losses to the win ratio (58% of all pairwise comparisons); NT-proBNP pairwise comparisons yielded the highest ratio of wins to losses (23.3% vs. 7.0%). The overall incidence of adverse events was similar in the acoramidis group and the placebo group (98.1% and 97.6%, respectively); serious adverse events were reported in 54.6% and 64.9% of the patients. CONCLUSIONS: In patients with transthyretin amyloid cardiomyopathy, the receipt of acoramidis resulted in a significantly better four-step primary hierarchical outcome containing components of mortality, morbidity, and function than placebo. Adverse events were similar in the two groups. (Funded by BridgeBio Pharma; ATTRibute-CM ClinicalTrials.gov number, NCT03860935.).

Rationale and design of the RAPID-WATER-FLOW trial: Radiolabeled perfusion to identify coronary artery disease using water to evaluate responses of myocardial FLOW.

OBJECTIVES: The objective of this study was to determine the diagnostic performance of 15O-water positron emission tomography (PET) myocardial perfusion imaging to detect coronary artery disease (CAD) using the truth-standard of invasive coronary angiography (ICA) with fractional flow reserve (FFR) or instantaneous wave-Free Ratio (iFR) or coronary computed tomography angiogram (CCTA). BACKGROUND: 15O-water has a very high first-pass extraction that allows accurate quantification of myocardial blood flow and detection of flow-limiting CAD. However, the need for an on-site cyclotron and lack of automated production at the point of care and relatively complex image analysis protocol has limited its clinical use to date. METHODS: The RAPID WATER FLOW study is an open-label, multicenter, prospective investigation of the accuracy of 15O-water PET to detect obstructive angiographic and physiologically significant stenosis in patients with suspected CAD. The study will include the use of an automated system for producing, dosing, and injecting 15O-water and enrolling approximately 215 individuals with suspected CAD at approximately 10 study sites in North America and Europe. The primary endpoint of the study is the diagnostic sensitivity and specificity of the 15O-water PET study using the truth-standard of ICA with FFR or iFR to determine flow-limiting stenosis, or CCTA to rule out CAD and incorporating a quantitative analytic platform developed for the 15O-water PET acquisitions. Sensitivity and specificity are to be considered positive if the lower bound of the 95% confidence interval is superior to the threshold of 60% for both, consistent with prior registration studies. Subgroup analyses include assessments of diagnostic sensitivity, specificity, and accuracy in female, obese, and diabetic individuals, as well as in those with multivessel disease. All enrolled individuals will be followed for adverse and serious adverse events for up to 32 hours after the index PET scan. The study will have >90% power (one-sided test, α = 0.025) to test the hypothesis that sensitivity and specificity of 15O-water PET are both >60%. CONCLUSIONS: The RAPID WATER FLOW study is a prospective, multicenter study to determine the diagnostic sensitivity and specificity of 15O-water PET as compared to ICA with FFR/iFR or CCTA. This study will introduce several novel aspects to imaging registration studies, including a more relevant truth standard incorporating invasive physiologic indexes, coronary CTA to qualify normal individuals for eligibility, and a more quantitative approach to image analysis than has been done in prior pivotal studies. CLINICAL TRIAL REGISTRATION INFORMATION: Clinical-Trials.gov (#NCT05134012).

Cardiovascular Testing in the United States during the COVID-19 Pandemic: Volume Recovery and Worldwide Comparison.

Purpose: To characterize the recovery of diagnostic cardiovascular procedure volumes in U.S. and non-U.S. facilities in the year following the initial COVID-19 outbreak. Materials and Methods: The International Atomic Energy Agency (IAEA) coordinated a worldwide study called the IAEA Noninvasive Cardiology Protocols Study of COVID-19 2 (INCAPS COVID 2), collecting data from 669 facilities in 107 countries, including 93 facilities in 34 U.S. states, to determine the impact of the pandemic on diagnostic cardiovascular procedure volumes. Participants reported volumes for each diagnostic imaging modality used at their facility for March 2019 (baseline), April 2020, and April 2021. This secondary analysis of INCAPS COVID 2 evaluated differences in changes in procedure volume between U.S. and non-U.S. facilities and among U.S. regions. Factors associated with return to prepandemic volumes in the United States were also analyzed in a multivariable regression analysis. Results: Reduction in procedure volumes in April 2020 compared with baseline was similar for U.S. and non-U.S. facilities (-66% vs -71%, P = .27). U.S. facilities reported greater return to baseline in April 2021 than did all non-U.S. facilities (4% vs -6%, P = .008), but there was no evidence of a difference when comparing U.S. facilities with non-U.S. high-income country (NUHIC) facilities (4% vs 0%, P = .18). U.S. regional differences in return to baseline were observed between the Midwest (11%), Northeast (9%), South (1%), and West (-7%, P = .03), but no studied factors were significant predictors of 2021 change from prepandemic baseline. Conclusion: The reductions in cardiac testing during the early pandemic have recovered within a year to prepandemic baselines in the United States and NUHICs, while procedure volumes remain depressed in lower-income countries.Keywords: SPECT, Cardiac, Epidemiology, Angiography, CT Angiography, CT, Echocardiography, SPECT/CT, MR Imaging, Radionuclide Studies, COVID-19, Cardiovascular Imaging, Diagnostic Cardiovascular Procedure, Cardiovascular Disease, Cardiac Testing Supplemental material is available for this article. © RSNA, 2023.

Safety of Catheter Ablation Therapy for Atrial Fibrillation in Cardiac Amyloidosis.

Background Despite the high burden of atrial fibrillation in cardiac amyloidosis (CA), the safety of catheter ablation therapy in CA is not well established. We sought to examine short-term safety outcomes following atrial fibrillation ablation in patients with CA compared with matched patients with dilated cardiomyopathy (DCM). Methods and Results Using data from the National Inpatient Sample, we identified all hospitalizations for atrial fibrillation ablation from the fourth quarter of 2015 through 2019. Admissions for CA and DCM were matched in a 1:5 ratio using propensity scores based on the following sociodemographics: age, sex, race or ethnicity, payor, median income, comorbidities, and hospital characteristics. We compared in-hospital outcomes between both cardiomyopathies. We identified 1395 unweighted hospitalizations (representing 6750 national hospitalizations) for atrial fibrillation ablation, out of which 45 (3.2%) were admissions for CA. Compared with DCM, patients with CA were older (72.9 versus 65.1 years), had a higher burden of prior stroke (20.0% versus 8.6%) and chronic kidney disease (53.3% versus 33.6%), and were less likely to have a prior implantable cardioverter-defibrillator (4.4% versus 23.0%). We successfully matched 42 CAs to 210 DCM hospitalizations. After matching, there was no difference in total complications (14.3% versus 10.5%, P=0.60), length-of-stay (3.1 versus 2.1 days, P=0.23), home disposition (97.6% versus 96.2%, P=0.65), and total charges ($137 250 versus $133 910, P=0.24). Conclusions In this nationally representative study of atrial fibrillation catheter ablation in CA, short-term safety outcomes and complication rates were similar to a propensity score-matched cohort of DCM. Further studies exploring long-term safety outcomes are needed.

Multi-center study of inter-rater reproducibility, image quality, and diagnostic accuracy of CZT versus conventional SPECT myocardial perfusion imaging.

BACKGROUND: Cadmium-zinc-telluride (CZT)-based detectors exhibit higher diagnostic sensitivity in myocardial perfusion imaging (MPI) than conventional Anger-MPI for detection of coronary artery disease (CAD); however, reduced specificity and diagnostic accuracy of CZT-MPI were observed. This study aims to compare these different camera systems and to examine the degree of inter-rater reproducibility among readers with varying experience in MPI. METHODS: 83 patients who underwent double stress/rest examinations using both a CZT and conventional SPECT cameras within one visit were included. Anonymized and randomized MPI-images were distributed to 15 international readers using a standardized questionnaire. Subsequent coronary angiography findings of ten patients served as a reference for analysis of sensitivity and specificity. RESULTS: Image quality was significantly better in CZT-MPI with significantly lower breast attenuation (P < 0.05). CZT-MPI exhibited higher sensitivity than Anger-MPI (87.5% vs. 62.5%) and significantly reduced specificity (40% vs. 100%). Readers experienced with both camera systems had the highest inter-rater agreement indicating higher reproducibility (CZT 0.54 vs. conv. 0.49, P < 0.05). CONCLUSIONS: Higher diagnostic sensitivity of CZT-MPI offers advantages in detection of CAD yet potentially of at the cost of reduced specificity, therefore it requires special training and a differentiated evaluation approach, especially for non-experienced readers with such camera systems.

Echocardiographic indices of left ventricular function and filling pressure are not related to blood pool activity on pyrophosphate scintigraphy.

BACKGROUND: Pyrophosphate (PYP) imaging has a high diagnostic accuracy for transthyretin cardiac amyloidosis (ATTR-CA). Indeterminate findings are often reported due to persistent blood pool activity, presumed to be from low cardiac output. We evaluated the relationship between blood pool activity on PYP imaging and echocardiographic indices of cardiac function. METHODS: Clinical and imaging data of 189 patients referred for PYP scintigraphy were evaluated. All patients underwent planar imaging and SPECT (diagnostic standard). Among those with a negative PYP SPECT, persistent left ventricular blood pool activity on planar images was inferred by a visual score ≥2 or a heart-to-contralateral (HCL) ratio ≥ 1.5. Absence of blood pool activity was inferred when both visual score was < 2 and HCL was < 1.5. Left ventricular ejection fraction (LVEF), global longitudinal strain (GLS), stroke volume index (SVi), and left atrial pressure (LAP) were calculated from standard transthoracic echocardiograms. RESULTS: ATTR-CA was present in 43 (23%) patients. Among those with a negative PYP SPECT, 11 patients had significant blood pool activity. Patients with ATTR-CA had a lower LVEF, SVi, and GLS, with a higher LAP, compared to those without ATTR-CA. Among those without ATTR-CA, there were no significant differences in these parameters. CONCLUSION: Approximately 8% of patients with a negative PYP SPECT have significant blood pool activity. Measures of cardiac function are not different among those with and without blood pool activity. PYP SPECT should be routinely performed in all patients to avoid false image interpretation.

Accuracy and Reproducibility of Myocardial Blood Flow Quantification by Single Photon Emission Computed Tomography Imaging in Patients With Known or Suspected Coronary Artery Disease.

BACKGROUND: Single photon emission computed tomography (SPECT) has limited ability to identify multivessel and microvascular coronary artery disease. Gamma cameras with cadmium zinc telluride detectors allow the quantification of absolute myocardial blood flow (MBF) and myocardial flow reserve (MFR). However, evidence of its accuracy is limited, and of its reproducibility is lacking. We aimed to validate 99mTc-sestamibi SPECT MBF and MFR using standard and spline-fitted reconstruction algorithms compared with 13N-ammonia positron emission tomography in a cohort of patients with known or suspected coronary artery disease and to evaluate the reproducibility of this technique. METHODS: Accuracy was assessed in 34 participants who underwent dynamic 99mTc-sestamibi SPECT and 13N-ammonia positron emission tomography and reproducibility in 14 participants who underwent 2 99mTc-sestamibi SPECT studies, all within 2 weeks. A rest/pharmacological stress single-day SPECT protocol was performed. SPECT images were reconstructed using a standard ordered subset expectation maximization (OSEM) algorithm with (N=21) and without (N=30) application of spline fitting. SPECT MBF was quantified using a net retention kinetic model' and MFR was derived as the stress/rest MBF ratio. RESULTS: SPECT global MBF with splines showed good correlation with 13N-ammonia positron emission tomography (r=0.81, P<0.001) and MFR estimates (r=0.74, P<0.001). Correlations were substantially weaker for standard reconstruction without splines (r=0.61, P<0.001 and r=0.34, P=0.07, for MBF and MFR, respectively). Reproducibility of global MBF estimates with splines in paired SPECT scans was good (r=0.77, P<0.001), while ordered subset expectation maximization without splines led to decreased MBF (r=0.68, P<0.001) and MFR correlations (r=0.33, P=0.3). There were no significant differences in MBF or MFR between the 2 reproducibility scans independently of the reconstruction algorithm (P>0.05 for all). CONCLUSIONS: MBF and MFR quantification using 99mTc-sestamibi cadmium zinc telluride SPECT with spatiotemporal spline fitting improved the correlation with 13N-ammonia positron emission tomography flow estimates and test/retest reproducibility. The use of splines may represent an important step toward the standardization of SPECT flow estimation.

DSPECT-specific normative limits for left ventricular size and function.

BACKGROUND: Differences in spatial resolution and image filtering between the solid-state DSPECT and traditional Anger SPECT (ASPECT) cameras are likely to result in differences in LV measurements. However, DSPECT-specific normal values are not available. The traditional approach of using patients deemed to have a low (< 5%) probability of coronary artery disease for the derivation of normative values has a number of limitations. We used healthy organ-donor subjects without known disease or medication use for derivation of normal values. METHODS: Subjects were 92 consecutive kidney or liver donors who underwent single-day rest (5 mCi)-stress (15 mCi) Tc-99m sestamibi-gated SPECT myocardial perfusion imaging (MPI) on the DSPECT camera for pre-operative evaluation and had normal perfusion and LV function. Exclusion criteria included any known cardiac disease or medications. LV measurements were made on the post-stress supine stress images using QGS®. RESULTS: Of 92 subjects (mean age 54.4 ± 15.0 and 39% men), mean EF ± 2SD for women and men was 77.2% ± 14.1% and 70.0 % ± 14.7%, respectively. Mean end-diastolic volume ± 2SD for women and men was 67.0 ± 32.2 mL and 99.6 ± 51.6 mL (indexed 38.3 ± 17.2 mL/m2 and 48.1 ± 25.9 mL/m2), respectively. Mean end-systolic volume ± 2SD for women and men was 16.1 ± 15.7 mL and 31.2 ± 29.2 mL (indexed 9.2 ± 8.8 mL/m2 and 15.0 ± 14.2 mL/m2), respectively. Mean LV wall volume ± 2SD for women and men was 95.9 ± 26.0 mL and 112.0 ± 48.8 mL (indexed 55.0 ± 13.8 mL/m2 and 54.1 ± 24.6 mL/m2), respectively. CONCLUSION: We report DSPECT-specific LV measurements from normal subjects from which limits of normality can be derived for clinic use. Organ donors who undergo pre-operative MPI are a suitable cohort for the derivation of normal values.

A Validated Model to Identify Patients With Low Likelihood of High-Risk Coronary Artery Disease Anatomy.

In stable coronary artery disease (CAD), revascularization improves outcomes only for patients with high-risk coronary anatomy (HRCA). We sought to derive and validate a prediction model, incorporating clinical and exercise stress test characteristics, to identify patients with HRCA. We conducted a retrospective analysis of patients undergoing exercise stress testing at Cleveland Clinic (2005 to 2014), followed by invasive coronary angiography within 3 months. We excluded patients with acute coronary syndrome, known CAD or ejection fraction <50%. HRCA was defined as left main, 3-vessel, or 2-vessel disease involving the proximal left anterior descending artery. Clinical and stress test predictors of HRCA were identified in a multivariable logistic regression model, internally validated with 1,000-fold bootstrapping. The model was then externally validated at the University of Pittsburgh Medical Center (2017 to 2019). The model was derived from 2,758 patients with complete data. HRCA was identified in 418 patients (15.2%) in the derivation cohort. The model consisted of 10 variables: age, male gender, hypertension, hypercholesterolemia, diabetes mellitus, family history of premature CAD, high-density lipoprotein, chest pain, exercise time, and Duke Treadmill Score. Bias-corrected c-statistic was 0.79 (95% confidence interval 0.77 to 0.81) with excellent calibration. In all, 762 patients (27.6%) had a predicted probability and observed prevalence of HRCA <5%. In the validation cohort, the model had a c-statistic of 0.79 (95% confidence interval 0.74 to 0.85) and 210 patients had an observed prevalence of HRCA <5% (40%). In conclusion, an externally validated prediction model, based on clinical characteristics and exercise stress test variables, can identify stable patients with CAD who have HRCA.